Volume 83, Issue 12 p. 2602-2604
COMMENTARY
Free Access

Biomarkers in solid organ transplantation

Teun van Gelder

Corresponding Author

Teun van Gelder

Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Correspondence

Professor Teun van Gelder MD, PhD, Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Tel.: +31 (0)1 0703 3202; Fax: +31 (0)1 0703 2400;

E-mail: [email protected]

Search for more papers by this author
First published: 07 September 2017
Citations: 6

Abstract

Recipients of solid organs such as the kidney and heart are treated with standard immunosuppressive regimens, and personalized medicine has not yet reached the clinic for this patient population. Biomarkers potentially will allow treatment regimens to be adjusted, according to the needs of the individual patient. Biomarkers may reflect the degree of immunosuppression of the immune system, or they may reflect early damage to the transplanted organ.

Personalized medicine is the ultimate goal of many physicians, including transplant physicians. In daily practice, the vast majority of transplant recipients are treated with the same combination of immunosuppressive drugs, at the same dose or with the same target drug concentrations 1. The focus is on therapeutic drug monitoring, and drug concentrations are measured at regular intervals. Based on these measurements, doses of calcineurin inhibitors (ciclosporin and tacrolimus), mechanistic target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) and (in some centres) mycophenolate mofetil are adjusted. Patients are subdivided according to immunological risk, and, depending on an assessment of low, intermediate or high risk for rejection, they will receive low-dose or high-dose treatment. This represents stratified medicine at best, and is still far from true personalized medicine.

Biomarkers potentially will allow treatment regimens to be adjusted, according to the needs of the individual patient 2. A much sought-after application of biomarkers in the transplant field is the assessment of the degree of immunosuppression. A drug concentration that leads to sufficient immunosuppression to prevent acute rejection in one patient may cause over- or under-immunosuppression in another. A test that has been referred to as an ‘immunometer’ should reflect the degree of immunosuppression, ideally in a donor-specific setting 3. After stimulation of recipient peripheral blood mononuclear cells with irradiated donor cells, read-outs of measures such as cytokine production, lymphocyte proliferation or expression of activation antigens on T lymphocytes could be used for monitoring. Although for some of these tests there are statistically significant associations with the incidence of acute rejection, or drug-related toxicity, none of these tests has proven to have sufficient positive and negative predictive value to be used in daily practice, and this represents a clear unmet clinical need. In the first months after transplantation, the immunometer would allow for guided stepwise increases in the immunosuppressive load, for those patients in whom the ex vivo immunological test would show under-immunosuppression. In the long-term follow-up of transplant recipients, there is a need to find the lowest possible dosages that will prevent rejection, and stepwise dose reductions could be supported by assays that show low-grade alloreactivity. With this approach, the high incidence of malignancies and infectious complications in patients on long-term immunosuppression may be reduced. An important population in this regard is elderly transplant recipients (above 65 years of age). Kidney transplantation has been shown to be an effective therapy for this age group. However, the immunosuppressive therapy for elderly patients is likely to be different to that for younger patients, considering the effect of ageing on the immune response 4, 5.

An alternative approach is to assess the biological activity of the immunosuppressive drugs on the target enzyme 6. Direct determination of target enzyme activity would provide a straightforward pharmacodynamic approach to evaluating the effect of the immunosuppressant in the individual patient 2. As an example, for mycophenolic acid, the activity of inosine monophosphate dehydrogenase can be measured 7. In general, such pharmacodynamic assays are labour intensive and costly, and cross-validation of the assay systems between laboratories has proven to be challenging. As a result, the prospective assessment of the clinical utility of this approach in larger patient populations is not yet available, despite the solid rationale for this type of biomarker.

Early detection of damage to the transplanted organ would offer the opportunity to intervene before irreversible damage has been caused. This will then lead to prolonged allograft survival. Several biomarkers are under investigation. One of the more recently investigated biomarkers is donor-derived cell-free DNA (dd-cfDNA) in the blood of the transplanted patient. At present, rejection of transplanted kidneys is detected by repetitive measurements of serum creatinine in the blood of the recipient. When serum creatinine levels rise, this may be because of an acute rejection, and a biopsy is then taken to prove histologically that a rejection is indeed the cause of the deterioration of renal function. However, creatinine starts to rise only when considerable damage has been done, and upward changes in the creatinine level are not specific for rejection. Protocol biopsies, at regular intervals after transplantation, can also be carried out to detect subclinical rejection episodes. However, these invasive biopsies are associated with high cost (and bleeding) complications, and are inconvenient both for the patient and the transplant team. Repetitive monitoring of dd-cfDNA can be done in large numbers of patients, in a non-invasive way, at relatively low cost. Recently, Bloom et al. 8 reported high negative predictive values for the detection of antibody-mediated rejection at a cutoff of 1.0% dd-cfDNA in a kidney transplant population. For patients after heart transplantation, where a serum marker like creatinine is lacking altogether, the added value of monitoring dd-cfDNA may be even larger than in kidney recipients. In heart transplant patients, the dd-cfDNA test would be a great improvement on the repetitive collection of endomyocardial biopsies to check for rejection.

Chemokines and cytokines also have the potential to be used as either diagnostic or prognostic biomarkers in patients following organ transplantation. Various stimuli, including brain death, ischaemia and reperfusion, are involved in early injury to the graft, and chemokines and cytokines play an important role. At later stages, chemokines and cytokines serve as chemoattractants for effector cells to move from the circulation to the injured organ. Investigation of the pathophysiology of this process has shown that only a few chemokines and their receptors play a key role, opening the potential to use these as biomarkers. One of the most promising chemokines in this regard is chemokine C-XC motif ligand 10 (CXCL10). This is involved in the recruitment of activated T lymphocytes to the site of inflammation, leading to infiltration and inflammation of the transplanted kidney. Previously, Schaub et al. 9 showed that urinary CXCL10 levels were significantly increased in patients with subclinical tubulitis compared with patients with normal renal histology. By contrast, several other urinary chemokines and tubular injury markers were not, or were only marginally distinctive across these patient groups. In addition, Jackson et al. 10 found that CXCL10 levels in urine were higher in adults and children experiencing either acute rejection or BK virus infection, compared with stable allograft recipients or patients with non-inflammatory causes of graft dysfunction.

The paper by Millan et al. 11 reports the results of a multicentre study on two urinary biomarkers. They found that urinary levels of both microRNA-155-5p (miR-155-5p) and CXCL10 showed a gradual upregulation in the period before an acute rejection was detected. Following treatment of the rejection, the miR-155-5p decreased again. It is known that miR-155 activates proinflammatory pathways, and several groups have studied the potential for monitoring circulating miR-155-5p levels to detect immune activation at an early stage. Clearly, urinary samples can be obtained easily, at repetitive time points after transplantation. The study of Millan et al. included 80 patients, of whom eight developed one or more rejection episodes, and larger series of patients are needed better to assess the sensitivity and specificity of these biomarkers. Furthermore, it is crucial that methods used for biomarker analysis are well standardized and that cross-validation between laboratories is done on a regular basis.

Competing Interests

T.v.G. has received lecture fees from Roche, Chiesi and Astellas Pharma, and consulting fees from Astellas, Novartis, Teva and Sandoz.